Your Digest for Sunday, Mar 03, 2024 10:59 PM


Sick Sinus Syndrome

AKA sinus node dysfunction.


ReceptorSitesAutonomicNervousSystem.jpg


    - aminophylline is a complex of (theophylline and ethylenediamine) 

Source

Pneumoconioses

Asbestosis Silicosis Berylliosis
Primary from mining;
Secondary exposure from using in manufacturing
Sand blasting etc Electronics manufacture
Fibrous form of Magneiusm Silicate SiO2 crystals ?Beryllium
Two Forms: Chrysolite - white asbestos, serpentien fibers - less harmful.
Crosydolite - blue asbestos, straight fibers, more harmful
Pleural plaques 20 to 30 years after exposure - most on rib associated surfaace of pleura
Benign effusions
Diffuse pleural thickening
Mesotheliomas
Bronchial Carcinomas
SiO2 crystals persist cause necrosis of phagocytosing macrophages -> enzymes release -> lung damage. (cessation of exoposure doens't hald lung damage);
Macrophage toxicity predisposes to post primary tuberculosis.
Lower lobe predilection Upper lobe fibrosis with lymph nodes which can calcify Upper lobe predilection.
asbestosis.png SilicosisUpperLobeEggShellCalcification.png

Causes of dominant R wave in V1

#2016GM-APR/Q01
RVH, Right sided Heart, RBB, Posterior MI

[!INFO] Summary

LBBB RBBB
Always pathological Can be benign
Causes LAD No effect on axis
Affects MI diagnosis No effect on MI diagnosis

normalQRScomplex.png

[!TIP] Mnemonic: It seems that increase in ventricular afterload can cause ipsilateral bundle branch blocks.
? cause of LAD in LBBB?
?is it because The counterbalancing effect of RV depolarization on the axis is lost as the RV depolarizes later??
Verapamil is a suitable alternative for adenosine if it it contraindicated.

[!INFO] AV nodal blocking drugs
Source: Harrison's
Mnemonic: AV nodal Blocking drugs : AVB -> Adenosine, verapamil, beta blockers (after trying vagal maneuvers)
(+? others)
AVNodeBlockingDrugs.png


[!INFO] Mnemonics:
Adenocarcinoma : Acchis
SQCs : Smokers
4. Diagnosis: By anti-P/Q-type voltage-gated calcium channel (VGCC) antibody testing and high frequency RNS (repetitive nerves stimulation)
5. Targeted therapy for symptomatic LEMS with 3,4-diaminopyridine is usually first line.
6. Refractory cases : immunosuppressants and plasma exchange.



HypercalcemiaSymptomsMnemonic.png

[!TIP] Hypercalcemia: Abdominal groans, psychich moans and renal stones.


Comparison of ABPA, EGPA and Hypersensitivity pneumonitis

Allergic bronchopulmonary aspergillosis
[[passMedicine Summaries#Hypersensitivity pneumonitis (HP)|Hypersensitivity Pneumonitis]]

Features ABPA
EGPA (Churg strauss)
Hypersensitivity Pneumonitis
Presentation Presents as poorly controlled asthma Can present with Difficult to control asthma
Clinical pearls Can be unmasked with monteleukast
Blood and serology Eosinophilia,
IgE levels always positive. Skin prick test for aspegillus is +ve.
Eosinophilia +
pANCA +ve
No eosinophilia
CD8+ predominant BAL aspirate
CXR Xray changes – migratory but persistent infiltrates. Proximal bronchiectasis, Upper lobe fibrosis if recurrent, Flitting pulmonary infiltrates CXR – non specific CT – centrilobular nodules.
Clinical features Fever, wheeze, cough Vasculitic features: mononeuritis multiplex, Rapidly proliferating glomerulonephritis, Tender subcutaneous nodules Acute: Fever, cough, No wheezing Chronic: SOB, fatigue, dyspnoea Crackles
Treatment Steroids + itraconazole + voriconazole Responds well to steroids Steroids + allergen avoidance

Complications of ileal resection


| Metformin | Biguanide | Insulin sensitiztion Reduce hepatic gluconeogenesis.It activates AMPK (AMP activated protein kinase) | GI side effects Lactic acidosis (risk in renal/liver/heart failure – contrindications) No weight gain May reduce apetite, STOP when eGFR < 30 | Reduced GI B12 absorption The usual first line agent, can be combined with other | Lower FBS by about 50 mg/dL Lowers HbA1C by about 1% |
Mechanism of action: Increases intracellular c-AMP potentiated insulin secretion.




After initial detection on the FBC, the investigation of choice is immunophenotyping by flow cytometry to reveal cell surface markers typical of CLL, including CD5, CD19 and CD20.

Background physiology of lymphocytes

LymphocyteOrigin.png
Source-YouTube
Source-YouTube
Source-YouTube

MHC I MHC II
Present on ALL nucleated cells Presenton APCs
Binds CD8 receptor Binds CD4 receptors
Stimultes Cytotoxic T cells Stimulates T helper cells

Natural killer cells

Chronic lymphocytic leukemia features


GVHD can occur after allogenic haemotopoietic cell transplantation or with solid organs containing lymphoid tissue. (Bowel transplant was one example)
GVHD arises when immune cells transplanted from a non-identical donor graft into the recipient (host), recognize the host cells as "foreign," thereby initiating a graft-versus-host reaction.

    - **Dermatitis** - painful, pruritic rash.  (not vessicles like in the mnemonic) 
- ![RashOfGraftVsHostDisease.png](RashOfGraftVsHostDisease.png)

  1. Progressive multifocal leukoencephalopathy (PML) ^13ac5c

#2016GM-OCT/Q29

Leishmaniasis: spectrum of disease.

Leishmaniasis has a wide spectrum of disease

At one end of the spectrum, mucosal leishmaniasis (ML) and leishmaniasis recidivans (LR) are caused by oligoparasitic disease associated with a marked cellular immune response.
The center of the spectrum consists of localized cutaneous leishmaniasis (LCL), which is the most common clinical presentation.
At the opposite end of the spectrum, diffuse cutaneous leishmaniasis (DCL) is caused by polyparasitic disease with a predominance of parasitized macrophages and no granulomatous inflammation.

Cutaneous leishmaniasis

This is the commoner form in Sri Lanka.
Symptoms:

Diffuse cutaneous

Musocal leishmaniasis

Visceral leishmaniasis

Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL); it is characterised by a macular, maculopapular, and nodular rash in a patient who has recovered from VL and who is otherwise well.

PKDLKalaAzar.png


  1. Hypercoaulable states can occur, specially with membranous nephropathy.
  2. Sepsis is a major cause of death due to loss of immunoglobulin -> pneumococcal infections
  3. Lipid abnormalities -> increased cardiovascular risk.
  4. ACEi / ARB are indicated for all patients with nephrotic range proteinuria.
  1. ?monoclonal deposition disease (presents with nephrotic range proteinuria

[!INFO] What "Effacement" means:
"Errasing, dissapearance". (like effacement of the cervix)

In this phenomenon, the normal interdigitated foot processes are finally reorganized into a broad flattened process like a paddle. The morphological process of the foot process effacement has not fully elucidated. Source
footProcesseffacementImageWhatIs.png

FSGS

FSGS is more likely with inflammatory conditions like SLE - PasTest

Primary FSGS Secondary FSGS
Sometimes responds to steroids, failure of steroids is common. Other immunosuppresants are used. Usually poor response to steroids. ACEi are better
Presents as massive proteinuria, haematuria and hypertension. Can be caused by any process which reduces functioning number of nephrons (eg. nephrectomy)
(nephrectomy, hypertension, gross obesity, IgA nephropathy, HIV, CMV, EBV)

FSGS pathology:

Source

proposedMechanismOfFSGS.png

in embryonic mice, parietal epithelial cells can migrate to the visceral layer and replace damaged podocytes (Right) but in the older mice, such replacement can't occur and results in sclerosis. (left)

FSGSHistology.png
Source

Minimal change Vs. FSGS

[!TIP]
MCD and FSGS are like cousins; FSGS is the evil cousin.

c | Electron microscopy image showing subepithelial electron-dense deposits (spikes)(black arrows) and basement membrane material between the electron-dense deposits (white arrows; 4,800×).



[!INFO] Stroke guidelines
[[NG-Management-of-Stroke-Book.pdf]]

Acute management of TIA

TIAacuteManagement.png
And along with the above, high intensity statin should be commenced immediately.

StrokeAcuteManagement.png

Secondary prevention of stroke:


Common problems in geriatric medicine are

Falls

#2016GM-OCT/Q25
#2016GM-APR/Q06
RiskFactorsForFalls.png


chestLeadViewsHeart.png

Leads with ST segment elevations Affected myocardial area Occluded coronary artery (cuprit)
V1–V2 Septal Proximal LAD.
V3–V4 Anterior LAD.
V5–V6 Apical / Lateral Distal LAD, LCx or RCA.
I, aVL Lateral LCx.
II, aVF, III Inferior 90% RCA. 10% LCx.

Right ventricular infarction

ECG-posterior-infarction-in-V2.jpg.webp
Posterior-leads-V7-V8-V9-ECG-placement.jpg.webp
- Isolated posterior wall STEMI is uncommon.
- Tall R waves in V1 and V2 are reciprocals of Q waves in the posterior wall.

Post MI prognosis

Killip class Features 30 day mortality
I No clinical signs heart failure 6%
II Lung crackles, S3 17%
III Frank pulmonary oedema 38%
IV Cardiogenic shock 81%


Coeliac disease

BCD + PRSTUvW
Bacterial overgrowh, Coeliac disease, Dermatitis herpetiformis
Parasites, Resection, Sprue, Tropical Srpue, Uv = radiation, Whipples

Symptoms

Complications

CoeliacDiseaseEndoscopy.png
coeliacDiseaseNoVilliCryptHyperplasia.png


AlcoholSafeUnits.png

[!INFO] It takes 1 hour to process 1 unit



PolycysticKidneyDisease.png

type 1 PCKD Type 2 PCKD
85% of cases 15% of cases
Presents earlier with renal failure

📑Management of PCKD


[!TIP] Mnemonic: Don't confuse with PSC - PBC has 'cirrhosis' in the name -> liver tissue is inolved -> interlobular bile ducts are involved.
#2016GM-OCT/Q30
enterohaemorrhagic (EHEC) (aka STEC - shiga toxin producing E coli)

But there are actually 5 types.

  1. ETEC causes watery diarrhea in resource-limited settings and is commonly found in food and water in areas without adequate sanitation
  2. EPEC (enteropathogenic) was the first E. coli pathotype identified as a causative agent of watery diarrhea primarily in infants and young children in resource-limited settings
  3. EAEC (enteroaggregative) is a causative organism of acute and chronic watery diarrhea in resource-limited and resource-rich regions
  4. EHEC/STEC produces Shiga-toxin and includes serotypes O157:H7, as well as others
  5. EIEC-induced diarrheal illness is uncommon due

Hook worm

Necator americanus ("American murderer")
and ancylostoma ceylonicum
HookWormAncylostoma.png


🔖Neurocysticercosis

#2022BSQ-OCT/Q5

cyst Scolex
Neurocysticercosis.png saginataVsSolium.png

taeniaSoliumLifeCycle.png

[!TIP] Mnemonic :"Solium polium" - solium = pork tapeworm.
Only pork tape worm causes cysticercosis
Taeniasis - tape worm in the intestine.

cysticercosis results from humans acting as 🔖accidental intermediate hosts for the parasite

[!INFO] Humans are the only definitive hosts for Taenia saginata, solium and asiatica.

[!INFO] Humans eat pig meat -> taeniasis, Humans eat pig poop -> cysticercosis
Ingesting uncooked pork -> ingestion of cysts in pig muscle -> intestinal tape worm infection in the human.
Ingesting eggs in faeces from infected human -> cysticercosis -> possible neurocysticercosis.
In cysticercosis, eggs hatch into larva which migrate through the host body into various tissues.

[!INFO] Phases of neurocysticercosis :
There are two forms; parenchymal (>60%) and extraparenchymal.

🔖Granuloma formation and patterns

A good detailed Source

[!TIP] overall summary
Granuloma formation is a histologic pattern of chronic inflammation.
Macrophages and tissue macrophages (histiocytes) usually form granulomas in order to eliminate an antigen which cannot be removed by a single macrophage.

  1. Epithelialization : where the cell membranes begin to interdigitate.
  2. Giant cell formation.
  3. This is when multiple macrophages fuse to form a giant cell with multiple nuclei.
    In addition, other types of immune cells are also recruited.

The type of immune cell that is recruited and the cytokines secreted by it will determine how the granuloma 'matures'.

Specially, Th cells have a significant role to play here.
When some granulomas mature, the central macrophages undergo necrosis ->

[!INFO] Exerpt from the summary of the article above:

Granuloma formation is a histologic pattern of chronic inflammation.
The particular pattern can suggestive of a particular disease

The pattern of inflammation can be classified in many ways. (necrotizing or not / Suppurative or not etc.)
This corresponds to the features of the granuloma after 'maturation'.
The prototypes are

effectsOfTCellsInGranulomas.png

monocytes in blood -> become macrophages in tissue (aka histiocytes)
histiocyte = tissue macrophage

Disease Pattern
Tuberculosis Caseating (i.e absolutely no cellular structure) granuloma with occasional Langhans giant cells
Leprosy Non caseating granuloma
Sarcoidosis Non caseating, abundant activated macrophages
Cat Scratch disease Rounded or stellate, central debris present.
Syphillitic gumma Central necrosis but with preserved cell outlines, plasma cell infiltrate
GPA (granulomatosis with polyangitis) presence of multinucleated giant cells, interstitial collagen alteration, and the presence of a polymorphous inflammatory infiltrate
Crohn's disease Occasional non caseating granulomas with dense fibrous infiltrate

[!INFO] Granuloma formation: Overview
Granulomas are formed when individual macrophages can't eliminate an antigen.
Then antigen presenting cells in the tissue recruit more macrophages from the circulation into the tissue.
Macrophages all clump around the antigen forming a granuloma.
The macrophages undergo a process called epithelialization where they take on the appearance of epithelial cells.
Their membranes begin to interdigitate and the nuclei swell.
Some of the macrophages will fuse to form Langhans giant cells.
The structure of the granuloma differs based on the triggering antigen.
In Tuberculosis, interferon gamma is a mediator of granuloma formation.
Other mediators like TNF-alpha are important in the formation of granulomas.

🔖Granulomatous diseases

  1. Naked granulomas - only sparse lymphocytic infiltrate at margin of granuloma; is a typical sarcoid lesions.
  2. Suppurative granulomas - have neutrophils at the center.
    1. Fungal causes
    2. Bacterial causes
    3. Atypical mycobacteria
    4. Pyoderma gangrenosum
    5. Parasitic : leishmaniasis
  3. Tuberculoid granuloma - caseous necrosis
    1. Usually in TB. Not in leprosy.
  4. Foreign body granulomas
    1. Berylliosis
    2. Silicosis
  5. Necrbiotic - contains altered collagen in the center. Also has acellular substances in the center.
    1. Divided into red and blue granulomas depending on the stain colour.
      1. Eosinophils are red.

Neutrophilic dermatoses

Pyoderma gangrenosum

Source

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that presents with rapidly developing, painful skin ulcers hallmarked by undermined borders and peripheral erythema. Epidemiological studies indicate that the average age of PG onset is in the mid-40s. Source

Pathergy is a feature.

[!INFO] Pathergy:
Pathergy is an exaggerated skin injury occurring after minor trauma such as bump, bruise, needle stick injury. A more severe injury, such as a surgical procedure, can result in persistent ulceration in a patient with pathergy. It typically occurs in patients with Behcet disease.
Pathergy occurs in :

DD for neutrophillic dermatosi: Sweet syndrome

Biopsy: INTENSE neutrophilic infiltrate with no evidence of infection or vasculitis.

#2017GM-APR/Q10

Associated diseases are

pyodermaGangrenosum.jpg

Treatment: steroids and immunosuppresants.

Sweet syndrome:

aka acute febrile neutrophilic dermatosis.

sweetSyndrome.png

🔖Metastasis in neoplasia

#2022BSQ-OCT/Q2

cancerMetz.png
Routes of malignant spread

  1. Seeding of body cavities : Typical of ovarian CA
  2. ❗Lymphatic spread : more typical or carcinoma
  3. Haematogenous spread: more typical or sarcoma.
    1. Arteries are less easily penetrated than veins. ❗Mets occur along venous drainage.
    2. All portal drainage goes to the liver; all caval blood flows to the lung -> these capillary beds are the main sites of metastasis in ❗haematogenous metastasis.
  4. ❗Thyroid and prostate CA metastasize via the paravertebral plexus -> vertebral metastases.
    1. bone metastases are more frequent in follicular and medullary thyroid cancers
  5. ❗Renal and hepatic CA like to grown inside veins:
    1. ❗Renal - renal veins and IVC
    2. ❗Liver hepatic veins and IVC
  6. Path of venous drainage alone doesn't account for the distribution of particular metastatic tumours; Some tumours have a propensity to metastasize to particular organs. This may be due to chemoattraction or expression of tissue specific adhesion molelcules by tumour cells.
    1. prostatic carcinoma preferentially spreads to bone,
    2. bronchogenic carcinomas tend to involve the adrenals
    3. and the brain, and neuroblastomas spread to the liver and bones.

🔖Brain tumours

Primary brain tumours are either

  1. Glial tumours - airising from glial cells
  2. Non glial - arising from everything else; nerves, blood vessels, glands etc.

Thyroid cancer

#2022BSQ-MAY Q27
Source:Medscape
thyroidCancer.png
originsOfThyroidCA.png
Follicular cells : Papillary, follicular and anaplastic CA.
Parafollicular C cells : Medullary CA. (C cells are neuroendocrine cells and they produce [[Hormone Physiology#Calcitonin|Calcitonin]]).

Differentiated thyroid cancers

[!INFO] Hot nodules are almost always noncancerous
However, the majority of thyroid nodules scanned are (Approximately 95 percent) are cold.
Most cold nodules are due to benign processes (>90%)
Cold nodules have an approximately 5% risk of being cancerous.
However, HOT nodules are almost never cancerous.

Both papillary and follicular CA are 3 times commoner in women.
Follicular develops at an older age.

Thyroglobulin is produced by differentiated thyroid CA. It can be used as a marker of recurrent after total thyroid ablation.

Papillary CA:

papillaryCA.png

Follicular CA

Are also usually cold nodules on radioiodine scan.
Commoner in iodine deficient areas.

Histology: encapsulated.
Follicular cells have a solid, trabercular or follicular growth pattern.
No characteristic nuclear features.
Differentiated from benign adenomas by

  1. capsular invasion
  2. vascular invasion

They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically

Follicular carcinomas have less tendency for local metz (nodes) but higher risk of distant mets.

Distant mets for both types occur to lung and bone.

Hurthle Cell carcinoma

Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
Makes up 2-3% of all thyroid malignancies.
Composed of distinct looking polygonal cells with acidophillic cytoplasm.
Associated with RAS mutation and RET/PTC oncogene.

[!INFO] Hurthle cells are seen in non malignant conditions as well
Hurthle cells are clasically seen in

Medullary thyroid Cancer (MTC)

2-3% of thyroid CA.
They are associated with familial MTC (FMTC) syndromes.
So much so that there is a clinical distinction between identification of patient familial MTC and diagnosis a new sporadic MTC.

Parafollicular C cells produce calcitonin -> elevated calcitonin is diagnostic of MTC.
Inheritance of all familial forms of MTC and MEN2 are #autosomalDominant .
RET proto-oncogene mutations are seen in all MTC syndromes.

Approximately 80% of individuals with a RET genetic variant will develop medullary thyroid cancer at some point in their lives.

FTMC is a subtype of MEN2. FMTC patients have less probability of the other cancers of MEN2 but higher probability of medullary thyroid CA.

Familial cases are multifocal and bilateral.
Sporadic cases are unifolcal.

Histology:

Treatment:
Lymph node metastasis is common.
Total thyroidectomy with lymph node clearance is done.
Prophylactic thyroidectomy is done in children diganosed with MEN2 syndromes.

MEN2 is divided into three subtypes: type 2A, type 2B and Familial Medullary thyroid carcinoma (FMTC).

  1. MEN2A - pheochromocytoma, hyperparathyroidism.
  2. MEN2B - MTC, phaechromocytoma, marfanoid habitus and galngioneuromatosis.
  3. FMTC - only MTC. (low risk of others)
Multiple Endocrine neoplasia syndromes

MultipleEndocrineNeoplasiaMENSyndromesMnemonic.png

In treatment of MEN, to avoid intra op hypertension, resection of pheochromocytoma should be done before MTC resection.

[!TIP] Mnemonic for MEN syndromes
පා පා පි
පා මේ ෆි
මා මේ ෆි
MENsyndromeMnemonics.png

Anapalstic thyroid CA

[!WARNING] A very, very bad cancer!
It is rare but has the worst prognosis of all thyroid CAs.
Occurs in older adults (60-70) -> older adult with a thyroid nodule could have a dangerous thyroid CA.
1 year survival is a dismal 20%. Median survival is 5-6 months.

Anaplastic CA grows rapidly. Many patients present with local invasion (unresectable tumours) or cervial lymph node metastasis.

On histology, the tumour retains feature so epithelial cells (presence of desmosomes) but there are large areas of necrosis and bleeding. There is high mitotic activity.

Bone tumours

Bone metastasis

Bone mets are commonest in spine, pelvis and thigh.

Osteolytic :

  1. Multiple myeloma
  2. RCC
  3. melanoma
  4. NSCLC
  5. Non Hodgkin Lymphoma
  6. thyroid cancer
  7. Breast cancer

Osteoblastic:

  1. prostate cancer,
  2. carcinoid,
  3. small cell lung cancer,
  4. Hodgkin lymphoma
  5. medulloblastoma.

Mnenomic for sclerotic bone lesion:
#2023BSQ-NOV/Q12

Regarding prostate CA:
Pathologic fractures do occur, although they are generally less frequent than in cancers with predominantly osteolytic disease
Source

Multiple myeloma – The classic bone lesions in multiple myeloma are purely osteolytic due to increased bone destruction and suppressed bone formation.
mmlyticlesions.jpg
Prostate cancer – Males with bone metastases from prostate cancer predominantly have osteoblastic (aka sclerotic) lesions with increased numbers of irregular bone trabeculae. Simultaneously, osteoclastic action is also increased.

Breast cancer - The great majority of breast CA produces osteolytic bone lesions, osteoblastic areas are also usually present

Renal cancer also commonly spreads to bone.

Atherosclerosis

#2022BSQ-OCT/Q08
Plaques are raised lesions in the blood vessel.
Filled with cholesterol and cholesterol esters.
#2020BSQ-JUL/Q32

Overview of atherosclerosis

[!INFO] Response to vessel injury
Vessel injury of any cause produces the same stereotyped response. Intimal thickening is a stereotypical response to vessel injury.
Mechanism: Intimal injury stimulates migration of smooth muscle cells from the media OR from circulating precursors!. They arrive in the intima, undergo mitosis and produces extracellular matrix, forming a 'neointima'. This is analogous to scar formation elsewhere. Neointimal smooth muscle cells are non contractile but can undergo mitosis and greater synthetic capacity. This altered activation of neointimal smooth muscle cells is driven by cytokines produced by platelets, macrophages, endothelial cells and circulating complement and coagulation factors. Cytokines involved are PDGF, FGF, TGF-alpha (Platelet derived growth factors, Fibroblast growth factors, TGF-alpha).
Removal of the harmful stimulus will revert the phenotype of neotintimal muscle cells to their non proliferative (medial smooth muscle is non proliferative) state but the thickening they have produced is irreversible.
Intimal thickening is also a normal part of aging but because of outward remodeling, does not narrow vessels.

Risk factors for atherosclerosis have roughly multiplicative effects. 2 factors -X2 risk, 3 factors X7 risk.
Risk factors:
Dietary:

Atherosclerosis requires two factors

  1. Endothelial dysfunction
    1. Involving altered gene expression (eg. incr. adhesion molecules) and increased permeability of endothelial cells.
    2. This allows migration of blood monocytes into the intima where they become macrophages.
  2. Increased lipids in the blood
    1. Cholesterol and it's esters are found inside plaques. They stimulate chronic inflammation in the intima in the presence of macrophages.

Anything that exacerbates these two factors will promote atherogenesis.

  1. Endothelial damage and dysfunction
    1. Smoking, hypertension, flow turbulence, some infection, ?toxins and drugs
  2. Hyperlipidaemia
    1. Any condition increases blood lipid levels ?Which lipids exactly - not HDL.

In the presence of lipids within the intima, macrophages become activated. When they 📑engulf lipids, they become foam cells.
Cytokines secreted by macrophages stimulate altered function and growth of smooth muscle cells of the media.
📑Smooth muscle cells proliferate and take on fibroblastic roles.
Smooth muscles + collagen produced by them form the fibrous cap of the plaque.

Plaques can

  1. obstruct vessels
  2. rupture -> thrombosis
  3. weaken the media -> aneurysms

Factors which make a plaque unstable:

  1. Thin fibrous cap
  2. Increased foam cells
  3. Increased lipid content etc.

[!INFO] The response to injury hypothesis of atherosclerosis

  1. Views atherosclerosis as a chronic inflammatory process.
  2. There is interaction of lipoproteins, macrophages, T lymphocytes to cause progression of the lesion
  3. Main components of atherosclerosis:
  4. Endothelial injury with ⬆ adhesiveness and ⬆ permeability - the main component. Atherosclerosis begins at intact but dysfunctional endothelium.
    1. Endothelial dysfunction is promoted mainly by altered haemodynamics and hypercholesterolemia.
      1. Haemodynamics: Turbulence; as occurs at ostia, branch points and posterior wall of the aorta. Laminar flow is protective via gene induction.
      2. Hypercholesterolaemia - 1) directly causes endothelial dysfunction, 2)Promotes inflammation by formation of oxidised LDL and cholesterol crystals
    2. Dysfunctional endothelium promotes adhesion of inflmmatory cells including macrophages (which engulf LDL to become foam cells) and T lymphocytes (which set up chronic inflammation).
  5. Platelet adhesion
  6. Monocyte / macrophage adhesion and adtivation
  7. lipid and lipoprotein accumulation
  8. Smooth muscle cell recruitment by mediators produced by platelets, macrophages
  9. Smooth muscle cell proliferation.

Morphology:

The majority of plaque ruptures occurs in the proximal and middle of coronary arteries and distal ruptures are rare.
Source

🔖Pancreatic physiology

pancreasPhysiology.png
#2022BSQ Q24

Secretin and CCK are endocrine hormones.
Secretin - role is to neutralize stomach effluent

Secretin stimulation test: Although secreting physiologically inhibits gastrin secretion, in the presence of a gastrinoma, secretin paradoxically increases gastrin secretion. This is the basis of the secretin stimulation test for gastrinoma.

🔖Selected gastrointestinal regulatory peptides

#2022BSQ-OCT/Q24

See table 32.4 K and C.
Secretin glucagon family
Vasoactive intestinal peptide (VIP) -> Secreted by enteric NERVES -> Neurotransmitter, Stimulates insulin release, splanchnic vasodildation and intestinal secretion of water and electrolytes; also relaxes smooth muscles, including the lower esophageal sphincter and colon
Mnemonic: VIP readies the stomach and gut receival of food.

Glucose dependent insulinotropic polypeptide - GIP - - From duodenum, gastric antrum and ileum - stimulated by intraduodenal glucose -> incretin effect. (produced by K cells)

GLP-1 - The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, to limit postprandial glucose rise. Secreted by L cells in the ileum and colon.

Humans have almost no L cells proximal to the ligament of treitz (i.e in the duodenum) Source

Secretion is likely triggered by glucose in the duodenum as well as the rest of the gut as well. Source

GLP-1 physiology

GLPPhysiologyMetabolism.png
Source
Only a small percentage of the produced GLP-1 reaches the liver and systemic circulation because of the action of DPP-IV.

[!TIP] Mnemonic: All of these hormones generally cause changes which promote digestion and absorption except for somatostatin

locationsGIpeptides.png

Somatostatin: somatostatin decreases endocrine and exocrine secretion and blood flow, reduces gastrointestinal motility and gallbladder contraction, and inhibits secretion of most gastrointestinal hormones.

Secretin: physiologic role increases pancreatic bicarbonate secretion and inhibits gastrin production. But in gastric CA, administration of secretin causes increased gastrin production. (paradoxically)

🔖Bilirubin physiology and elevations

BilirubinMetabolism.png

[!INFO] Elevated urobilinogen levels
#2020BSQ-NOV/Q04
Urobilinogen levels rise with increasing bilirubin production.
"Elevated urobilinogen levels may also be seen when the liver simply cannot remove urobilinogen from the portal venous blood, as occurs in severe liver disease, such as cirrhosis." - Source

bilirubinMetabolismOverview.png

[!INFO] Significance of active conjugated bilirubin secretion from hepatocytes
The active secretion of cojugated bilirugin into bile cannaliculi is rate limiting. But uptake of unconjugated bilirubin is very efficient.
Therefore, hepatocytes near the supplying veins will take up all the unconjugated bilirubin but may not be able to excrete all of it into the bile. Therefore, they reexcrete it into the sinusoids so that down stream hepatocytes can reuptake this conjugated bilirubin and help to excrete it into the bile canalliculi.
I.e more hepatocytes are recruited for excretion.
The transport proteins requried for reabsorption are affected in Rotor syndrome -> leads to conjugated and unconjugated hyperbilirubinaemia.(mostly conjugated)

Classification of causes of hyperbilirubinaemia

[!TIP]
Note how all the intrahepatic causes of jaundice cause conjugated hyperbilirubinaemia.
?? are the only causes of unconjugated hyperbiliribunaemia CN , Gilbert and haemolytic anaemias?

causesOfJaundiceHyperbilirubinaemia.png

[!INFO] DDx of conjugated hyperbilirubinaemia
And this table which Medscape made incredibly hard to copy.
ConjugatedHyperbilirubinaemiaCauses.png

Causes of unconjugated hyperbilirubinaemia

From Harrisons

  1. Haemolysis
  2. Ineffective erythropoiesis
  3. Defective conjugation - Criggler najjar and Gilbert
  4. Acquired conjugation defects
    1. It's possible in cirrhosis but usually, "conjugation is better preserved than other aspects of bilirubin metabolism like canalicular secretion".
    2. Gentamicin can inhibit UGT1A1 -> unconjugated hyperbilirubinaemia

🔖Complement system overview

#2019BSQ-OCT/Q54

The complement system consists of a set of plasma glycoproteins.Source.

What follows are several images of how the complement system works;
complementSystemOverview.pngSource

complementPathway.png

Main functions of the complement proteins

[!INFO] Functions of complement

complementSystem.svg
Source

[!INFO]
complementOverview.gif
C3a is an anaphylatoxin
C3b is an opsonin (it binds to foreign molecules) -> it tags microorganisms as foreign.

Activation of the 3 complement pathways

Classical pathway

Evolutionarily the newest but first to be discovered.

Alternative pathway

Evolutionarily the oldest
Basically, C3 is constantly being hydrolysed at low levels to form C3b but this is inactivated rapidly. If the C3b happens to bind to a pathogen, it become protected from inactivation and can trigger subsequent cascade activation.
The alternative pathway does not require antibodies.
It is triggered when C3b binds to bacterial polysaccharides and other endotoxins.

More details:

The alternative pathway of complement activation depends on spontaneous hydrolysis of C3 in plasma leading to the formation of C3 (H2O). This molecule binds to factor B. Subsequent activation by factor D results in the formation of C3 (H2O) Bb. This complex cleaves additional C3 to C3a and C3b constantly and at a low rate. In the presence of an activating surface (e.g. a bacterial wall), C3b is protected from inactivation by regulatory proteins like factor I and H. As a result, a more active alternative pathway C3 convertase - called C3bBb- is formed, which is further stabilized by properdin.Source

Then, the C3b particles formed by both pathways above goes on to form the C5 convertase by combining with various other complement factors.

[!INFO] C5 -> C5a (Most potent anaphylatoxin ) + C5b (initiator of MAC)

Diseases of complement deficiency

Source

[!TIP] Mnemonic :

🔖Causes of increased CPK

#2022BSQ-OCT/Q31
CPK = CK.
Creatine Kinase is a catalyst for the formation of ATP from ADP via transfer of phosphate from creatine phosphate (which is an energy reservoir for muscle.
It is a very good indicator of muscle breakdown and it's progression.
CPK is eliminated by the ❗Reticuloendothelial system❗. Serum level isn't elevated in kidney disease.

3 isoforms

🔖Urine cultures

We want to get urine samples which contain bacteria which have managed to enter the bladder. (bacteria colonize the distal urethra and genital mucosa)
Theoretical best sample is first voided urine of the day as bacteria have had time to multiply overnight and it is also the most concentrated sample.
Suprapubic taps should yield sterile urine in a healthy patient.

Prostatic massage should be done prior to urine sample correction in suspected if chronic bacterial prostatis is suspected. ❗Massage should be avoided in acute bacterial prostatits -> risk of bactiraemia!

Sample is cooled until it is sent to the lab to prevent bacterial multiplication affecting the colony count.

Urine microscopy

pyuria

8 cells / microL = 2-5 cells per High power Field.
Very high associated with urinary infection.

White blood cell casts - renal infection = could be pyelonephritis.

Causes of sterile pyuria:

Cardiac action potentials

normalActionPotentials.png
see [[SaltatoryConductionMechanism.png]]

Cardiac action potentials

![cardiacActionPotentials.png](cardiacActionPotentials.png)

Source: CVS physiology website.

pacemaker cells non pacemaker cells
No true resting potential
Continuous action potentials generated
Depolarization due to SLOW calcium current FAST Na mediated depolarization
If or "funny current" is a mixed sodium/potassium inward current.

Electrolyte effects on ECG

ECG changes in hyperkalemia :

#2020SBR-NOV/19
#2020BSQ-JUL/Q02

The pathophysiology of changes in hyperkalemia includes

hyperkalemiaECG.png
Boradening of the QRS complex is a feature (although not mentioned in the table below) Source

Level Changes Basis
5.5 - 6.5 📑 Tall t waves Repolarization abnormalities
6.5 - 7 📑 P wave widening and flattening, broadening of PR interval Progressive atrial paralysis
7.0 - 9.0 📑 Sinus brady, AV block, AF, conduction blocks ❗Conduction abnormalities
> 9.0 Sine wave ❗Peri arrest

In hyperkalemia, ECG changes progress from peaked T-waves to widened QRS and eventually to ventricular tachycardia, fibrillation or pulseless electrical activity arrest.  These progressive changes can correlate with rising potassium levels. For example, peaked T waves might correspond with a potassium level of approximately 6 mmol/L, whereas cardiac arrest generally occurs at higher levels.

Management of hyperkalemia

#2023SBR-NOV/Q24
read in K and C

Emergency: Calcium gluconate

Tall tented t waves - PR prolongation - Broad QRS - Sine wave pattern - asystole, VT, VF

Acute: Insulin + dextrose

Requires 1 - 2 hourly monitoring of plasma glucose.

Subacute management: Potassium binders

Hypokalemia

[!INFO] Mnemonic: Opposite of the hyperkalemic changes

EKG changes can include

The 'classic findings' are

The U-wave is a deflection following the T wave. Potassium levels that are critically low (<1.7 mmol/L) can lead to torsades de pointes or “twisting of the points”, a polymorphic ventricular tachycardia.

[!INFO] 📑U wave

Torsades de Pointes

[!INFO] Definition of Tosade de pointes
Torsade is defined as the combination of polymorphic ventricular tachycardia plus a prolonged QT-interval.
Source
Polymorphic VT is defined as ventricular tachycardia with varying QRS amplitute.

Pathophysiology: QT prolongation predisposes to 'after depolarizations' which can produce TdP

ventricularTachycardiaTorsadesDePointes.png
also [[torsadesDePointes.png]]

Causes of QT prolongation:

Congenital Drugs Other
- Jervell-Lange-Nielsen syndrome (includes deafness and is due to an abnormal potassium channel)
- Romano-Ward syndrome (no deafness)
- amiodarone, sotalol, class 1a antiarrhythmic drugs
- tricyclic antidepressants, fluoxetine
- chloroquine
- terfenadine
- erythromycin
- electrolyte: hypocalcaemia, hypokalaemia, hypomagnesaemia
- acute myocardial infarction
- myocarditis
- hypothermia
- subarachnoid haemorrhage
Management
  1. Magnesium sulfate bolus (4g of MgSO4) even if Mg level is normal
  2. Correct all electrolytes
  3. Stop all QT prolonging medications
    1. Quinidine, disopyramide, flecainide, haloperidol, chlorpromazine, TCAs + many others
  4. Amiodarone is the drug of choice for for treatment of haemodynamically unstable VT.
  5. Verapamil should never be used in VT - ?why
    F

Hypercalcaemia

The most common EKG finding associated with hypercalcemia is shortening of the QT interval. In severe cases, Osborn or J waves might be seen or ventricular fibrillation might ensue. Recognition of these EKG findings can prompt urgent treatment.

Hypocalcemia 🡫

The most common finding on EKG in patients with hypocalcemia is a prolonged QT interval.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.105.166563

doi.org/10.1016/0002-9149(63)90255-8

Hypermagnesaemia

#TODO

Hyponatremia and hypernatremia have no effect on the ECG.

Increased (hypernatremia) and decreased (hyponatremia) sodium levels do not have any effect on the ECG, nor cardiac rhythm, or impulse conduction. Source

🔖Tumour markers

#2021BSQ-JUL/Q31
TumourMarkers_2.png

Cholangiocarcinoma

[!TIP] GPT answer:
Certainly! Here is a list of common tumor markers and the tumors they are commonly associated with:

  1. Prostate-Specific Antigen (PSA) - Prostate cancer
  2. Carcinoembryonic Antigen (CEA) - Colorectal cancer, pancreatic cancer, lung cancer
  3. Alpha-fetoprotein (AFP) - Liver cancer, germ cell tumors, particularly testicular cancer
  4. CA-125 - Ovarian cancer (CA = carbohydrate antigen)
  5. CA 19-9 - Pancreatic cancer, colorectal cancer
  6. CA 15-3 - Breast cancer
  7. CA 27-29 - Breast cancer
  8. Human Chorionic Gonadotropin (hCG) - Germ cell tumors, particularly testicular cancer, ovarian cancer, ?lung CA
  9. Calcitonin - Medullary thyroid cancer
  10. Thyroglobulin - Thyroid cancer (papillary and follicular)
  11. Neuron-Specific Enolase (NSE) - Neuroendocrine tumors, small cell lung cancer
  12. Chromogranin A - Neuroendocrine tumors
  13. S-100 Protein - Melanoma, neuroendocrine tumors
  14. Human Epidermal Growth Factor Receptor 2 (HER2) - Breast cancer, gastric cancer
  15. Epidermal Growth Factor Receptor (EGFR) - Non-small cell lung cancer, colorectal cancer
  16. 5 HIA - carcinoid tumour
  17. Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells in the gut wall, especially the appendix.

BRCA1 and BRCA2 - breast and ovarian cancer.

Inflammatory bowel disease

[!TIP] A great summary!
Source

chron'sVsUlcerativeColitis.png
crohn'sUlcerativeColitisDistribution.png

[!INFO] Differentiation of disease is vital to determine the potential effectiveness of surgery!
resection is curative in UC but disease recurs after resection in Crohn's;
Mnemonic: "Colectomy is curative"

featuresOfCrohnsDisease.png

Feature Crohn's Disease Ulcerative Colitis
presentation Abdominal pain + perianal disease. (although colonic disease can cause PR bleeding) GI bleeding
Endoscopy Cobblestones + linear ulcers Diffuse continuous involvement, pseudopolyps
Radiography Fistulae No fistulae
Distribution (potentially mouth to anus) Terminal ileal involvement Or ileocolitis, skip lesions(+) No ileal involvement (backwash ileitis possible)
Rectal involvement Possible, may spare the rectum Rectum always involved
Pathology Transmural involvement(+) (wall to serosa), Granulomas (+) mucosal and submucosal inflammation
Serositis(+), Creeping fat Crypt abscessesCrypt abscesses are more common in UC than CD
Management Resection not curative Colectomy eliminates illness
Epid Develops in teen and twenties
Complications Intestinal obstruction / perforation
Extraintestinal manifestations Toxic megacolon!
Malabsorption (because UC involes only the colon)
Smoking effect Increased by smoking Reduced by smoking!
Appendisectomy Increases risk of CD Protective against UC (mnemonic: appendix connected to the colon)

[!INFO] NOTE! Crypt abssesses are present in both but more common in ulcerative colitis.

IBDCrohnsVsUlcerativeColitisGobletCells.png
crohnsNoSmokingMnemonic.png

Peak incidence for both is between 15-30 years. But disease can occur at any age.

Research shows smoking – specifically the chemical nicotine in tobacco – seems to both guard against ulcerative colitis (UC) and help ease symptoms.

[!INFO] 'Positive features' of Ulcerative colitis not seen in Crohn's disease

Extraintestinal manifestations of Crohn's disease IBD

crohn'sExtraintestinalManifestations.png
#2021SBR-NOV/Q08
Extraintestinal manifestations are common to both diseases.
Joint complications are the most common:
extraintestinalManifestationsIBD.png

  1. Migratory arthitis - appendicular skeleton. Parallels intestinal disease. Treatment of intestinal disease resolves arthritis.
  2. Perichonlangitis - seen on ERCP or MRCP.
  3. Kidney stones- seen in crohn's disease (?could be due to defective enterohepatic circulation of bile salts)
  4. Bowel inflammation -> ureteric obstruction and hydronephrosis
  5. Fistulas

Ileal resection can cause bile acid malabsorption -> diarrhoea.

Management options for IBD

Goal of treatment is to prevent recurrences and promote healing of existing lesions.

Crohn's disease

Induction of remission

Maintenance

Except for steroids, the others can be used for maintenance.

Ulcerative colitis

Induction of remission

Maintenance

#TODO

Primary sclerosing cholangitis

primarySclerosingCholangitis.png
onionSkinFibrosisPrimarySclerosingCholangitis.jpg

Primary Biliary Cirrhosis / Primary Biliary Cholangitis

#2021GM-JUL/Q39

[!TIP] PBC - the C can stands for Cirrhocis or Cholangitis.

[!TIP] When to suspect
Suspect in a middle aged woman with pruritus who has elevated ALP and possibly other autoimmune conditions.

[!TIP] Mnemonic: Don't confuse with PSC - PBC has 'cirrhosis' in the name -> liver tissue is inolved -> interlobular bile ducts are involved.
Middle aged, itchy woman - Karens
ALP is the only abnormal investigation

MCQ Discussion:
Most often diagnosed through routine screening.
Usually asymptomatic. -
But Fatigue is a prominent presenting symptom. Pruritus is an early and common sign. Icterus is late signs.

🔖Immunoglobulin / antibody classes

#2022BSQ Q49

Types of immunoglobulins and antibodies
IgG IgA IgD IgM IgE
typesOfAntibodies.png
typesAndActionsAntibodies.png
Source

🔖Insulin

#2022BSQ-OCT/Q40

Sources of insulin

Animal based : not commonly used.
Bovine insulin differs from human by 3 amino acids, porcine by 1 amino acid.

Pharmacokinetics

Regular insulin and NPH insulin are considered older insulins.
Their time to peak and duration of action don't mimic physiologic secretion.
insulinActionDuration.png
❗(U-100) denotes the usual concentration (100 U/ml).

Regular insulin

NPH insulin

Duration: Intermediate.
Suspension of human insulin, protamine and zinc. -> delays release of insulin into blood, also longer time to peak.
Patient must eat after the morning dose is given, to avoid hypoglycaemia.

Delivery :

mix immediately before injection and given at room temperature.
NPH insulin is a cloudy solution.
Can be mixed with regular or rapid acting insulins in the syringe.
Always draw up the regular(clear) insulin first to avoid contaminating the regular insulin with isophane insulin, thereby altering its pharmacokinetics.

U-500 insulin

Not regularly used nowadays, partly because of the advent of DPP-4 inhibitors.

Insulin analogs

made by recombinant DNA technology.
Substitution of amino acids produces rapid acting and long acting analogs.

Rapid acting insulins

Lispro, aspart, glulisine (and faster aspart, lipro-aabc)
Duration: (very short) duration and rapid onset

modifications were made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action

Insulin aspart- substitution of aspartic acid for proline at position B28.

Insulin lispro is identical to human regular insulin except for a lysine and proline at positions B28 and B29.

Insulin glulisine has a lysine and glutamic acid at positions B3 and B29 respectively.

Rapid acting insulins are more convenient.
U-200 lispro and U-200 lispro-aabc, are high concentration preparations which have some niche use cases.

Basal insulin analogs

Determir

Insulin detemir – Detemir is an acylated insulin; the fatty acid side chain allows reversible albumin binding as well as concentration-dependent self-association (ie, formation of dihexamers) that results in prolongation of action.
Determir is much less potent - so it is formulated in a 4:1 ratio. (1 Unit of determir contains four times as many insulin molecules as any other preparation of insulin)
❗Can't mix with rapid acting insulins.

Glargine

Glargine is identical to human insulin except for a substitution of glycine for asparagine in position A21 and by the addition of two arginine molecules to the amino terminus.

After subcutaneous administration, glargine precipitates in the tissue, forming hexamers, which delays absorption and prolongs duration of action.

Glargine, which is in an acidic solution, cannot be mixed with rapid-acting insulins, as the kinetics of both the glargine and rapid-acting insulin will be altered

Glargine has less nocturnal hypoglycemia than NPH insulin

Duration of action : 24 hours but some may need twice daily dosing as half life is 12 hours. Unlike glargine, determir has a small peak in it's concentration profile.

Higher concentration preparations of glargine (U-300) have an even flatter concentration curve with lower hypoglycaemic effect.

Degludec

form multimers from which monomers are release-> even longer duration of action.
Can mix with rapid acting insulins.

[!TIP] Degludec - the only long acting insulin that can be mixed with rapid acting insuline Mnemonic: Glue - glue it up.

Determinants of insulin efficacy

The absorption of the long-acting basal insulin analogs, glargine and degludec, do not appear to be significantly influenced by injection site


Insulin administration in the elderly

#2020BSQ-JUL/Q25
This Source and other articles in general seem to indicate that basal bolus regimes are too rigorous to follow for elderly people.
Morning basal insulin regimens may be recommended. Usually, for fasting hyperglycaemia, nocturnal basal dose is given.

Types of hypersensitivity

#2022BSQ Q48
#2022BSQ-MAY Q46

Hypersensitivity reactions refer to undesirable responses produced by the normal immune system - Source

typesOfHypersensitivity.png

[!INFO] Mnemonic
Type III - 3rd letter in alphabet - C for immune complexes.
[[Toxicology#Serum sickness]]

typesHypersensitivityReactions.png

Type 1 Type 2 Type 3 Type 4
commonest type Goodpasture syndrome, autoimmune anaemias, erythroblastosis faetalis [[2023-SEMPaper#Systemic Lupus Erythematosus SLE|SLE]], serum sickness, reactive arthritis, PSGN, [[2022 November SBR#Rheumatoid arthiritis|Rheumatoid Arthtiris]] second most common
Immediate hypersensitivity - eg analphylaxis 2-24 hours days to weeks 2 days
IgE (from plasma cells) mediated IgG and IgM - bind to own cell surface molecules -> complement activated IgG and IgM antigen antibody complexes Cell mediated - non antibody dependant - T cells, monocytes and macrophages
degranulation of mast cells and basophils complement mediated red cell agglutination and other cell lysis Cytokines which cause cell death and inflammation are released
Type Alternate name Examples Mediators
I Allergy (immediate) • Atopy    – Anaphylaxis    – Asthma    – Allergic rhinitis    – Angioedema    – Food allergy IgE
II Cytotoxic, antibody-dependent • Erythroblastosis fetalis • Goodpasture syndrome • Autoimmune anemias, thrombocytopenias IgG, IgM
III Immune complex disease • Systemic lupus erythematosus • Serum sickness • Reactive arthritis • Arthrus reaction Aggregation of antigens IgG, IgM Complement proteins
IV Delayed-type hypersensitivity, cell-mediated, antibody-independent • Contact dermatitis • TuberculosisChronic transplant rejection T cells, monocytes, macrophages

Type 5 hypersensitivity

Is when the produced antibodies have the property of stimulating receptors on cells. Best example is Grave's disease.
Source

[!TIP] Hypersensitivity Vs Autoimmune disease
Hypersensitivity is an abnormal immune response to a harmless stimulus. When the 'stimulus' is a self antigen, we call it autoimmunity.

Autoimmune diseases can be classified in the same way as hypersensitivity conditions. but IgE is not involved in autoimmunity.
so in the table[[2022 November SBR]] below, there is no "type I" in the autoimmune categories

🔖Autoimmune diseases examples

examplesAutoimmuneDiseases.png
Autoimmune diseases caused by antigens against cell surface receptors: [[moreAutoimmuneDiseases.png]]

Infectious diarrhoea

#2022BSQ Q54

Summary table of traveller's diarrhoea

overviewInfectiveDiarrhoea.png

Infection Typical presentation
Escherichia coli Common amongst travellers
Watery stools
Abdominal cramps and nausea
Giardiasis Prolonged, non-bloody diarrhoea
Cholera Profuse, watery diarrhoea
Severe dehydration resulting in weight loss
Not common amongst travellers
Shigella *Bloody *diarrhoea
Vomiting and abdominal pain
Campylobacter A flu-like prodrome is usually followed by crampy abdominal pains, fever and diarrhoea which may be bloody
May mimic appendicitis
Complications include Guillain-Barre syndrome
Amoebiasis Gradual onset bloody diarrhoea, abdominal pain and tenderness which may last for several weeks
Staphylococcus aureus Severe vomiting
Short incubation period
Bacillus cereus Two types of illness are seen

- vomiting within 6 hours, stereotypically due to rice
- diarrhoeal illness occurring after 6 hours
#2016GM-OCT/Q30

[!TIP] The types of E coli - "HIT"
enterohaemorrhagic (EHEC) (aka STEC - shiga toxin producing E coli)
enteroinvasive (EIEC)
enterotoxigenic (ETEC)
The first two cause bloody diarrhoea.

But there are actually 5 types.

  1. ETEC causes watery diarrhea in resource-limited settings and is commonly found in food and water in areas without adequate sanitation
  2. EPEC (enteropathogenic) was the first E. coli pathotype identified as a causative agent of watery diarrhea primarily in infants and young children in resource-limited settings
  3. EAEC (enteroaggregative) is a causative organism of acute and chronic watery diarrhea in resource-limited and resource-rich regions
  4. EHEC/STEC produces Shiga-toxin and includes serotypes O157:H7, as well as others
  5. EIEC-induced diarrheal illness is uncommon due

Diarrhoea in resource rich settings

[!INFO] A Great table!
[[diarrhoeaInResourceRichSettings.png]] <- A great table!

[!TIP] Watery diarrhoea
"Noninflammatory diarrhea is caused by the action of enterotoxins on the secretory mechanisms of the mucosa of the small intestine, without invasion" - Medscape.

Same day:

  1. Norovirus (mnemonic : N for 'naught' for day zero) ("winter vomiting bug" - also causes vomiting)
  2. clostridium perfringens
  3. possibly listeria (pregnancy, immunosuppression, extremes of age)

Next day:

  1. E coli - enterotoxigenic
  2. most other viruses - (1-3 days) diarrhoea in children, immunocompromised adults
  3. (including Rotavirus)

Same week

  1. [[Misc infectious diseases#Cyclospora cayatensis infection|Cyclospora infection]]

Weeks later

  1. Giardia 1 to 2 weeks later - day care, swimming pools, travel / camping.
  2. Cryptosporidium 2-28 days (upto 1 month after) - Associated with day care centers, swimming pools. (common in HIV patients)
  3. see [[HIV-AIDS#Selected aids defining illnesses]]

^5eaea3

[!TIP] Mnemonics: inflammatory diarrhoea
Fever, mucoid or bloody stools show infective diarrhoea:
"Can't Assume Everyone's Your Very Special Sidekick"
batmanAndRobin.jpg

Let's break it down:

  1. "Can't" - Campylobacter
  2. "Assume" -[[2023-SEMPaper#Amoebiasis|Amoebiasis]]
  3. "Everyone's" - E. coli
  4. "Your" - Yersinia
  5. "Very" - Vibrio parahaemolyticus
  6. "Special" - Salmonella
  7. "Sidekick" - Shigella

Most of these have P-incu of 1-3 days.
But, entamoeba - much longer- 1 to 3 weeks, yersinia - slightly longer- 4-6 days, E-coli 1-8 days.

Complications of dysentery include [[General medicine 3#Guillain barre|GBS]], [[2022-SBR-MAY#Reactive arthritis]]

management of campylobacter diarrhoea

Giardiasis

[!INFO] Giardiasis is one of the most common intestinal infections worldwide in both developed and developing countries

giardiaTrophozoite.png

Diarrhoea in resource poor settings

shigellaDiarrhoea.png

Epidemic diarrhoea

Main two pathogens of epidemic diarrhoea

  1. Cholera (secretory rice water diarrhoea) [[Misc infectious diseases#Cholera]]
  2. Shigella dysenteriae (bloody diarrhoea) - SD1 serotype. (inflammatory diarrhoea - blood + mucous)

epidemicDiarrhoeaPathogensCholeraShigella.png

Non epidemic diarrhoea

Commonest causes of non epidemic watery diarrhoea - E. coli.

[!TIP] mnemonic
Acute bloody diarrhoea
$$
{C^1S^2E^3}
$$

Commonest cause of non epidemic bloody diarrhoea - shigella flexneri (not dysenteriae)

Diarrhoea due to preformed toxins

#2021BSQ-NOV/Q37

Symptoms suggesting diarhoeal illness caused by preformed toxins:

Enterobiasis

strongyloidesVsEnterobius.png

🔖Strongyloidosis

#2020BSQ-NOV/Q50
frenchArmyVietnamStrongyloidosis.jpg
strongyloidesStercoralis.png

[!INFO] How to understand the life cycle;
parasite has a free living cycle and parasitic cycle.
So adult worms can be found in the environment and the intestinal lumen of hosts.
Eggs can be deposited a) In the host intestine and b) in the environment.
Eggs always produce rhabditiform larvae.
Eggs -> rhabditiform larvae -> filariform larvae. (Infective stage) (autoinfection or otherwise).
If excreted with stool, rahbditiform larvae can go on to develop into adult sexual stages which produce more eggs in the free living cycle.

Female Adult worm (who live embedded in the submucosa of the small intestine) lays eggs.

It has been thought that the L3 larvae migrate via the bloodstream and lymphatics to the lungs, where they are eventually coughed up and swallowed. However, L3 larvae appear capable of migrating to the intestine via alternate routes (e.g. through abdominal viscera or connective tissue)

Symptoms:

Respiratory : Dry cough - about 1 week after infection
Abdominal pain, bloating, intermittent constipation and diarrhoea - about 3 weeks or later after infeciton (due to infection of the small intestine)
Skin: Itchy rash at site of entry; recurrent red rash along thighs and buttocks. - Larva currens (pathognomonic of Strongyloidiasis).
Disseminated life threatening infection can occur in immunosuppressed people.
Eosinophilia(+).
Can cause [[2021-SBR-November#Loffler syndrome / Loeffler syndrome | Loeffler syndrome]]

Management:

Ivermectin has been shown to be superior to albendazole.

Ivermectin: binds selectively and with high affinity to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells of microfilaria.

Albendazole and other similar drugs inhibit the beta tubulin of worms (intracellular cytoplasmic structural protein) -> immobilization and death.

🔖Echinococcosis

#2020BSQ-NOV/Q50
? Dog tape worm
A 2-7mm long small tape form whose definitive host is the dog.
Intermediate host is animals like sheep.
Sheep tissues have cysts which are infective when ingested by a dog.
The adult forms in the dog then shed eggs with faeces which are usually ingested by the sheep, but can also be ingested by humans.
One ingested, the eggs hatch the the larvae penetrate the intestinal wall and take up residence in the tissues.
In the tissues, they from hydatid cysts.
The cysts usually grow for many years and are asymptomatic until they cause symptoms due to pressure effects.
However, if a cyst ruptures, it can cause analphylaxis, or a milder fever, and dissemination of the parasites within.
Treatment: Surgery or less invasive procedures like PAIR (percutaneous aspiration, injection of chemicals and reaspiration).

[!TIP] Sheepdog
mnemonicSheepDogEchinococcus.jpg

echinococcosis.png

Trichinellosis

#2020BSQ-NOV/Q50
trichinellosisMnemonic.jpg
trichinella.png
Image of skeletal muscle encysted and liberated trichinella parasite.
Trichinella_LifeCycle.gif

Treatment:
Albendazole and mebendazole for about 14 and 10 days respectively. Treatment should be started within first few days of infection, or else, larvae will migrate into skeletal muscle and treatment will not completely eliminate the infection.

Trichiuris

Trichiuris trichiura - the human whipworm
Trichuris_LifeCycle.gif
trichiurisTrichiuraImages.png

[!INFO] Delayed action "haal atey"

Diagnosis:

Treatment:

Ascariasis

ascarisMnemonic.png

ascarisLumbricoidesAdultAndEggs.png
ascarisLumbricoides.png

Treatment:

Skull base fracture

#2022BSQ Q51
Skull base fracture and associated injuries; Source
NCBI article <- good link
Cranial nerve injuries: Page 1079 of Moore's clinical anatomy.

Posterior fossa signs: battle signs, haemotympanum, loss of gag reflex and accessory nerve palsy.

Sjogren syndrome

#2022GM Q14
#2021GM-JUL/Q17

[!TIP] Mnemonic
SR4 : Sjogrens => RoLa+ / RF+ / RTA / Raynaud

Pathogenesis: Autoimmune disease affecting exocrine glands.

In most cases, Sjogren syndrome is only 'irritating' and not dangerous.

Can occur as a primary disorder or secondary to another rheumatic disease.

Symptoms are classified mainly as

  1. Exocrine gland symptoms
    1. Predominant symptoms of Sjogren's syndrome are
      1. oral dryness (affects salivary glands)
      2. and dry eyes. - assessed by Schirmer test < 5mm/min. (filter paper used to assess tear production)
  2. Extra glandular symptoms
    1. Skin :
      1. Xerosis (dryness)
      2. Raynaud's phenomenon
      3. Cutaneous vasculitis: Palpable purpura is the commonest manifestation.
    2. Muskuloskelatal: Arthralgria, myopathy, fibromyalgia.
    3. Associated with autoimmune thyroiditis.
    4. Lungs - interstitial lung disease; upper and small airway involvement; Patients have ❗cough and dyspnoea.
    5. Peripheral neuropathy
    6. Depression / mood changes/ mild cognitive impairment (maybe due to poor sleep)
    7. Mild anaemia and leukopenia
    8. Other autoimmine diseases
      1. Myasthenia gravis
      2. Autoimmune hepatitis/ pancreatitis.
      3. Autoimmune thyroiditis
    9. Increased incidence of Non Hogdkins B lymphoma.
    10. Can cause renal involvement - hypokalemia is common secondary to distal renal tubular acidosis [[2021-SBR-November#Renal tubular acidosis]] with K+ wasting.
    11. Rare complication of Sjogren syndrome during pregnancy : congenital heart block.
    12. ?Dysphagia with abnormal oesophageal motility.

Spectrum of disease:

Mild disease : just dry eyes and mouth; Requires diagnostic criteria to be fullfilled to diagnose SjD.

Severe disease:
A severely affected patient may have florid salivary gland enlargement, adenopathy, antibodies to the Ro/SSA and La/SSB antigens, cryoglobulinemia, hypocomplementemia, a propensity to develop non-Hodgkin lymphoma, and other extraglandular disease manifestations.

90% are positive for Rheumatoid factor: Kumar and Clark

Epidemiology: Most Commonly occurs in women aged 50-60 years old.

Associated conditions

Keratoconjuntivis sicca - term for the occular manifestations of Sjogrens.
Mikulicz syndrome: Parotid and lacrimal gland enlargement;

Diagnostic criteria:

Biopsy showing focal lymphocytic infitrate of labial salivary glands. Termed Focal lymphocytic sialadenitis.

Objective test: Focal lymphocytic sialadenitis score >= 1;

Anti Ro/SSA and anti La / SSB positivity suggests Sojgren's disease.

Background of systemic autoimmune disease. -
The most common associations are SLE and Rheumatoid arthritis.

🔖Pathogenesis of ascites in Cirrhocis

#2020SBR-JUL/Q18

HemodynamicscirrhosisAscitesPathogenesis.gif
This flow chart shows the mechanism of activation of various vasoactive systems in cirrhosis.
pathogenesisAscites.png
![Pasted image 20231021010143.png](Pasted image 20231021010143.png)
Several haemodyanic and vascular changes occur which contribute to the formation of cirrhocis.

Vascular:

Multiple mediators have been studied as sources of the systemic vasolidation but the most important one seems to be increased NO synthesis.

inhibition of synthesis of NO in rats restores normal arterial pressure.

? cause for increased NO
Portal hypertension -> increased portosystemic shunting -> decreased hepatic clearance of bacterial toxins / DNA absorbed from GI tract.

mediated by vascular changes:
Splanchnic vasodilation
Renal artery vasoconstriction
(and also pulmonary vasodilation)

Ascites: The pathological accumulation of fluid in the peritoneum.
Development of portal hypertension is the first step and is essential for the formation of ascites in cirrhocis.

Older theories of ascities formation : undefill theory and overflow theory. Modern arterial vasodilation hypothesis fits better with data.

Arterial vasodilation theory of ascites formation

A portal pressure >12 mmHg appears to be required for fluid retention
Portal hypertension is not simply due to mechanical obstruction of the portal system. It occurs due to increased flow from the splanchnic arteries.

See hypothesis-highlights on UpToDate

SAAG

#2022GM Q32
Serum 'to' Ascites Albumin gradient
SAAGserumToAscitesAlbuminGradient.png
SAAG > 11g/L - low protein in ascitic fluid => Suggest portal hypertension as cause; (i.e transudate)
SAAG < 11g/L - high protein in ascitic fluid (or low serum protein) => Exudate (?malignancy)

❗Low ascitic fluid protein may increase the risk of SBP as there are no opsonins in the fluid to combat infection.

SAAGinterpretation.png

algorithmAscites.png

Liver transplantation

Indications for liver transplantation

  1. Acute liver failure of any cause
  2. Chronic hepatic failure with Childs grade > C or MELD > 20;
    1. hepatopulmonary syndrome can be reversed by hepatic transplantation.
  3. Primary biliary cholangitis
  4. Chronic hepatitis B is HBV DNA negative or falling; recurrence of infection is prevented by HBIG and nucleoside analogues.
  5. Autoimmune hepatitis
  6. Alcoholic
  7. Metabolic disorders - haemochromatosis, Wilsons, Alaph a antitrypsin deficiency
  8. NASH cirrhocis

Management of Ascites

#2020SBR-JUL/Q18

Measures to reduce ascites:

Bronchiectasis

#2022GM Q21
#2017GM-OCT/Q10

Review of airway histology

Respiratory epithelium - ciliated pseudostratified columnar epithelium.

airwayHistologyStructure.png
Note the presence of smooth muscle and it's decreasing thickness as the airways become smaller.

Bronchioles - intralobular airways < 1mm in diameter arising roughly after the 10th generation of branching.

Epidemiology

Commoner in women.
Increases with age; marked increase after 60 years.

Pathology

Bronchiectasis is the permanent dilation of bronchi and
bronchioles caused by destruction of the muscle and the
supporting elastic tissue
, resulting from or associated with
chronic necrotizing infections. It is not a primary disease
but rather secondary to persisting infection or obstruction
caused by a variety of conditions

bronchiectasisPathogenesis.png

Once patients develop bronchiectasis, most commonly isolated organisms are haemophillus and pseudomonas and streptococcus pneumoniae.

Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding on spirometry. ;
$$
\LARGE{Obstruction = ↓\frac{FEV_{1}}{FVC}}
$$

See [[Lung function tests#Obstructive vs. restrictive diseases]]

Morphology

Diagnosis:

Clinical and CT:
CT features that are reliable signs of bronchiectasis:

Causes of bronchiectasis and basis of disease

Common causes

Obstruction - tumour, lymph nodes, aspiration etc. <- impaired drainage
Inherited disorders -
Cystic fibrosis #autosomal-Recessive <- impaired clearance of mucous
Kartagener syndrome <- Ciliary impairement
Autosomal recessive #autosomal-Recessive
Situs inversus, chronic sinusitis, and bronchiectasis; Underlying pathology is primary ciliary diskinesia. Kartagener Xn is a subset of primary ciliary diskinesia (in which patients may not have situs inversus).
Screening test -> patients have low levels of nasal nitric oxide.

Immunoglobulin deficiencies <- recurrent infection
Necrotizing of suppurative pneumonia - staph aureus or klebsiella <- scarring and impaired clearance; ?exagerrated neutrophil response

Cystic fibrosis

Other causes

Young syndrome - similar to CF but no evidence of CF; rare diagnosis nowadays.
Associated with two rheumatic disorders - Sjogren syndrome and Rheumamtoid arthritis.
[[General Medicine 1#Allergic bronchopulmonary aspergillosis|Allergic bronchopulmonary aspergillosis]] - ? central bronchiectasis

Management

Antibiotics for exacerbations
Control of acute bleeding with bronchoscopic local therapy or bronchial artery embolization.
Refractory disease: surgical therapy - ? resection

🔖Immunodeficiency syndromes

Typical presentations and associated defects in the immune system

#2022BSQ-MAY/Q49

Defect Presentation
Antibody deficiency Recurrent sinopulmonary infection / meningitis / chronic GI infections (esp. capsulated organisms - H. Influenza, N. meningitidis, S. pneumonae)
Granulocyte (neutrophil) defects Recurrent soft tissue infection
Cell mediated immunity (esp. T cells) Infection with Viruses, intracellular pathogens, fungi (CMV, EBV, mycobacteria, candida, [[HIV-AIDS|cryptococcus]],[[HIV-AIDS#Pneumocystic jirovecii pneumonia|pneumocystis]] )

Skin infections, in isolation, are not usually indicative of an underlying primary immunodeficiency.
Chronic mucocutaneous candidiasis - ussually begins in childhood; associated with several immunodeficiency states; usually doesn't show systemic infection with the fungus.
Recurrent herpevirus infection / reactivation -> These individuals should be evaluated for underlying T or natural killer (NK) cell dysfunction. See -> [[2021 Basic Sciences July#Natural killer cells]]
 ***
 However, recurrent respiratory tract infections in combination with more serious infections are a classic presentation of antibody deficiencies.
 ***
~~>  
 - Isolated urinary tract infections are more suggestive of anatomic defect than immunodeficiency.
 - Relapsing, recurrent, and/or progressive enterocolitis due to common enteropathogens, such as Giardia, enteroviruses, cytomegalovirus, and campylobacter, are associated with underlying hypogammaglobulinemia and/or T cell immunodeficiency.
 
 - Recurrent Neisseria meningitidis meningitis -> Deficiency of one or more of the terminal complement components (C5, C6, C7, C8, C9) . Low complement levels may be due to either congenital complement deficiency or acquired diseases, such as systemic lupus erythematosus.
 - Immunoglobulin deficiency disorders or impaired reticuloendothelial function resulting from splenectomy or hemoglobinopathy are associated with an increased risk of bacteremia and meningitis due to encapsulated pathogens.
 - Marked elevation of serum IgE with multisystem infections -> Job syndrome
~~

Defect Outcome Organism
low gamma globulin recurrent enterocolitis and ? sinopulmonary infections Giardia, enteroviruses, CMV, campylobacter
Terminal complement Recurrent neisseria meningitis
Ig or RET Recurrent encapsulated pathogen infection
Selective IgA deficiency Usually asymptomatic; can present with recurrent mucosal pyogenic infections

Immunoglobulin / antibody deficiencies

Usually due to defects in B lymphocytes -> not enough antibodies produced.

Recurrent sinopulmonary infections and persistence of gut pathogens.
Leads to bronchiectasis and chronic diarrhoea with malabsorption.

Common variable immunodeficiency

[!INFO] Commonest significant antibody deficiency affecting children and adults.

Diagnosed at: 20 and 45 years of age.

? etiology - few are inherited. Pattern may by #autosomalDominant with low penetrance or #autosomal-Recessive - UpToDate

There is

Complications:

Chronic giardia infections with malabsorption can occur.

Treatment is IVIG.

Selective IgA deficiency

Commonest primary immune deficiency.
Individuals are usually asymptomatic. -> treatment is only antibiotics as needed.
Can present with recurrent mucosal pyogenic infections.

Agammaglobulinaemia

#2021BSQ-JUL/Q24
Also called hypogammaglobulinaemia.

Mutation of the BTK gene impairs B cell maturation -> causes low or absent mature B cells -> severe hypogammaglobulinaemia.
Commonest inheritance: #x-linked-recessive with mothers being carriers. #autosomal-Recessive inheritance is seen in ? 50%. - confirm

Manifestation: recurrent sinopulmonary infections.(From 6 to 12 months of age, otitis media, sinusitis, bronchitis, and pneumonia).
Common pathogens: Encapsulated pyogenic bacteria Haemophillus influenzae and strep pneumoniae.

Treatment: repeated IVIG transfusions or stem cell transplant.

Complement deficiency

[[2022-November#Complement system overview]]
Impaired alternative pathways -> non specific impairement -> bacterial infections.

Impaired classical pathway -> increased infection and increased immune complex deposition -> SLE, vasculitis, glomerulonephritis etc.

MAC -> neisseria infections.

Severe combined immunodeficiency - SCID

#2022BSQ-MAY/Q49

Immune response to fungi

[[ImmuneResponsesTofungalpathogens.pdf]]
Not as well understood as bacteria and viruses.
Pattern recognition receptors (PRR) on antigen presenting cells are triggered by fungal cell components.
This causes intracellular signalling of the APC which promotes phagocytosis and stimulates killing mechanisms.
The adaptive immunity to fungi is mediated by CD4+ Th1 cells with produce interferron gamma and CD4+ Th17 cells which produce IL-17. They drive killing by innate effector cells like marcophages and neutrophils.

So overall,

  1. neutrophil defects cause systemic candiasis
  2. T cell defects cause mucocutaneous candidiasis.

🔖Neutrophil defects

opsonizationOpsoningAndPhagocytes.png
![Pasted image 20231013091119.png](Pasted image 20231013091119.png)

[!INFO] presentation
> Is with recurrent and severe bacterial (Staphylococcus, pseudomonas, salmonella, Nocardia) and fungal (candida, Aspergillus) infections, most commonly of the respiratory tract and skin.

defectsInNeutorphilFunction.png

#2020BSQ-JUL/Q29

  1. [[2022 May Basic Sciences#Chronic granulomatous disease|Chronic Granulomatous disease]] <- a defect in neutrophil killing.
  2. Leukocyte adhesion deficiency -> a defect in 'firm' adhesion of leukocytes to vessel walls caused by defect in integrins. #autosomal-Recessive
  3. Hyper IgE syndrome - Job's syndrome
  4. Schwachman-Diamond syndrome ^226faf
  5. Chediak-Higashi syndrome

🔖Acquired neutrophil defects / neutropenia

🔖OPSI - overwhelming post splenectomy infection

Splenectomy leaves the patient vulnerable to infection by capsulated organisms.

  1. Streptococcus pneumoniae
  2. Haemophillus influenzae
  3. Neisseria meningititis

[!TIP] Mnemonic: Capsulated organisms : Have No Sex.
encapsulatedOrganismsMnemonic.jpg

More than half of those with OPSI die.

Why specifically encapsulated organisms?

Encapsulated organisms are resistant to phagocytosis without opsonization.
❗The spleen is a major site of early IgM production.

IgM memory B cells produce IgM to promote the clearance of polysaccharide-encapsulated bacteria.

Although the total B lymphocytes remain intact, a significant fall in the levels of memory B cells and switched B cell proportions are usually encountered 150 days post-splenectomy. This acts as a particular predisposition to infections caused by polysaccharide-encapsulated bacteria and is responsible for a diminished immunological response to polysaccharide vaccines
Source

However, even after opsonization, the bacteria must be phagocytosed. Splenic macrophages are a major contributor to this phagocytosis.
So in asplenia, there is impaired IgM production and thus opsonization and also impaired phagocytosis.

[!INFO] primary Vs. secondary immune response:
Primary-and-secondary-antibody-responses-typify-the-adaptive-immune-response-to-antigen.pngSource

Amyloidosis

#2019BSQ-OCT/43
"Amyloid" was meant to describe the starch like properties of the substance. Initially described as "waxy" and "lardaceous".

Normally soluble proteins are deposited extracellularly as beta pleted fibrils.

Subtypes of amyloidosis

There are 18 different types of systemic and 22 localized forms of amyloidosis

The four most common causes of systemic amyloid deposition are

  1. AL amyloidosis
  2. ATTRwt - wild type transthyretin amyloidosis
  3. Hereditary (familial) amyloidosis
  4. AA amyloidosis (caused by serum amyloid A protein)
  5. And Dialysis associated amyloidosis
    1. Dialysis-related amyloidosis (DRA) is a disabling disease characterized by accumulation and tissue deposition of amyloid fibrils consisting of beta2-microglobulin (beta2-m) in the bone, periarticular structures, and viscera of patients with end-stage kidney disease. Beta2-m is a component of the major histocompatibility complex that is present on cell surfaces and is normally cleared by glomerular filtration

[!INFO] AL Vs AA : importance of differentiating
AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.

Type Constituent
AL Amyloidosis Deposition of Ig Light chain fragments
Transthyretin amyloidosis
AA amyloidosis serum amyloid protein - acute phase reactant; Most common form in resource limited countries - occurs due to chronic inflammation

Other forms of amyloidosis:

Diagnosis

Histological : Fat pad biopsy (less risk of bleeding)
Organ biopsy is needed if a specific organ is involved.

When Congo red stains binds to amyloid protein, it produces apple green birefringence.
GlomerularAmyloidosis.jpg
Looks similar to DM nephropathy but the staining characteristics are different (DM nephropathy is PAS and silver stain positive)
AppleGreeBirefringence.jpg

Cutaneous manifestations of amyloidosis

AL amyloidosis

MGUSprogression.png

[!INFO] MGUS to myeloma

AL amyloidosis is Associated with plasma cell dyscrasia (multiple myeloma, waldenstrom macroglobulinemia)

📑Symptoms and signs

There is multisystem amyloid deposition

Treatment

Bortezomib based induction <- a myeloma directed therapy
Melphalan
Haematopoietic cell transplantation.

Prognosis

This disorder has a poor long-term prognosis, with cardiac or hepatic failure, and infection being the major causes of death
Earlier detection confers better outcome.

AA amyloidosis

The most common organ affected by AA amyloid is the kidney (approximately 80 percent of patients -> causes nephrotic syndrome.

Seen in Chronic inflammatory disorders include rheumatoid arthritis, inflammatory bowel disease and untreated familial Mediterranean fever.

AA amyloidosis may complicate chronic diseases in which there is ongoing or recurring inflammation, such as rheumatoid arthritis (RA), spondyloarthritis, or inflammatory bowel disease; chronic infections.

Symptoms

SImilar to AL (but cardiomyopathy is rare)
GI involvement: similar to AA amyloidosis

Treatment

In untreated patients, AA (secondary) amyloidosis carries a significant risk of mortality due to end-stage kidney disease, infection, heart failure, bowel perforation, or gastrointestinal bleeding.
Successful treatment of the underlying inflammatory process improves kidney function.
Treatment of the underlying condition can control but not cure amyloidosis.
For transthyretin type amyloidosis, liver transplant is definitive therapy as the liver is where transthyretin is made.

Spondyloarthritis (SpA)

Spondylos = greek for vertebrae

common features

Uveitis
The presence of leukocytes in the anterior chamber of the eye is characteristic of anterior uveitis.
The presence of leukocytes in the vitreous humor - intermediate uveitis
Evidence of active chorioretinal inflammation -> posterior uveitis

Characteristic radiographic features

Sacroiliac joint:

Syndesmophytes and changes of spondylitis in the spine, which are most often detected in more longstanding disease.

A syndesmophyte is a bony growth originating inside a ligament, commonly seen in the ligaments of the spine, specifically the ligaments in the intervertebral joints leading to fusion of vertebrae.

Inflammatory osteoproliferative lesions in the spine are called syndesmophytes (marginal and non-marginal), and degenerative osteoproliferative lesions are called osteophytes. Syndesmophytes are more vertically oriented than osteophytes.

syndesmophytesVOsteophytes.png

Syndesmophyte Osteophyte
Arise from calcification withn ligaments Arise from bone (vertebral bodies)
Seen in inflammatory (spondylo) arthropathies See in Osteoarthritis
Source

Subtypes of SpA

[!TIP] Mnemonic: RePsAnkIb

[!INFO] Mnemonic: PAIR
Mnemonic for spondyloarthritis : PAIR ->

EnthesisAsAnOrganAnatomy.png

Ankylosing spondylitis

#2022GM Q25
#2022GM Q27

Ankylosing = stiffness or fixation of a joint by disease

typicalAnkylosingSpondylitisPatient.jpg
Affects teens to early 30s, male >> female (5:1).
Pathology: lymphocyte and plasma cell infiltration of the attachments of ligaments. (enthesitis)

Some terminology: not super important
ankySpondyTerminology.png

Pathogenesis of Ankylosing spondylitis

SourceGreat article!

HLA-B27

[!INFO] Key points

Clinical features of AS

ankiSpondylosisJointsMnemonic.png

[!TIP] mnemonic:
Extra-articular complications all begin with A:

Diagnosis

"Plain x-ray of the sacroiliac joints is the most useful investigation in establishing the diagnosis."

The sacroiliac joint is actually a synovial joint with hyaline on the sacral surface and fibrous cartilage on the iliac surface Source.

Management of Anky Spondi

Aplastic anaemia

#2022GM Q30

Congenital

Acquired

Hepatosplenomegaly and lymphadenopathy are rare.

Bone changes seen in various diseases

boneChangespassMedicine.png


Bradykinin

[!TIP] Mnemonic : BPH - bradykinin, prostaglandin and histamine act together.

ClostridiumDifficileStoolSamples.png
| | |

[!INFO] Up to 1 year post op for valve replacement, staph epidermidis >> staph aureaus.
[[aetiologicAgentsInfectiveEndocarditis.png]]

HACEK denotes Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae.


- They are also some of the oldest antiepileptics. Newer drugs have better pharmacokinetics. 
- The narrow spectrum AEDs mostly work for specific types of seizures (such as focal, absence, **or** myoclonic seizures). 
- Broad spectrum AEDs additionally have some effectiveness for a *wide variety of seizures* (focal **plus** absence myoclonic seizures).

AntiepilepticSpectrum.png
Source
- Mnemonic: cOllECtIvE (COLLECTIVE IS SIMILAR TO 'BROADLY') (LeCo-VoLT)
BroadSpectrumAEDsMnemonic.png


Generalized Anxiety disorder

Source

Treatment: See [[#Treatment for GAD and panic disorder]] below.

Panic disorder

Source
PD is defined by the DSM-5 as recurrent panic attacks that include characteristic symptoms and lack an obvious trigger followed by concern about another attack lasting for at least 1 month.
Panic attacks that are nocturnal or lack fear require a more extensive workup.
Commonest symptoms is palpitations.
"panic attack": an intense surge of fear or discomfort which peaks within minutes which are associated with many physical symptoms including chest pain.

Treatment for GAD and panic disorder

Source


If > 8 hours since ingection, NAC is given rather than methionine.

[!INFO] Paracetamol
1,4,8,16
Gastric lavage 1 hour.
Activated charcoal 4 hours. Levels also at 4 hours.
Before 8 hour, methionine can be given and is as effective as NAC.
After 8 hours, give NAC.
Liver damange unlikely if NAC started within 8 hours.

Criteria for liver transplantation

King's College Hospital criteria for liver transplantation (paracetamol liver failure)

almost identical to cinchonism (quinine toxicity).

Organophosphate and carbamate poisoning

Carbamate toxicity

#2022SBR-MAY/Q16
#2016GM-APR/Q05

Organophosphate poisoning

SLUDGE/BBBSalivation, Lacrimation, Urination, Defecation, Gastric Emesis, Bronchorrhea, Bronchospasm, Bradycardia, and Miosis

 - Mainly Proximal Muscle weakness: characteristic neurological findings including neck flexion weakness, decreased deep tendon reflexes, cranial nerve abnormalities, proximal muscle weakness, and respiratory insufficiency
 - Complete resolution occurs in 2-3 weeks if the patient receives ventilatory support
 - Intermediate syndrome is rarer with carbamate poisoning Source but it can occur.

Several weeks after exposure
Characterized by distal weakness and sensory loss first in the lower limbs; may progress proximally and affect upper extremities.
This occurs due to inhibition of neuropathy target esterase (NTE) by organophosphates.
Carbamates are generally though to not cause neuropathy because the acetylcholinesterase bone is reversible- but some cases have been reported. Source


Non alcoholic fatty liver disease (NASH)/(NALFD)


Feature Hepatitis B Hepatitis C
Epidemiology est. 220 million carriers est. 70 million carriers
Virus type DNA SS-RNA
Transmission Vertical(during birth) is common
Hep B in children is a main issue
Vertical transmission is rare
Blood + products Blood + products, needle sharing
Vaccine Present Rapid mutations -> No vaccine
Clinical course Acute: 70% subclinical (anicteric)
 30% icteric hepatitis
1% - fulminant hepatitis
Overall, in vast majority disease is self limited.
Acute: Asymptomatic but 10% will have flu like symp.
Overall about 25% will clear the infection spontaneously.
Chronic: 5% of acute infection becomes chronic Chronic: 90% of asymptomatic acute infection becomes chronic.
50% of symptomatics become chronic.
Chronic infection 4 phases:
HBeAg+, normal ALT, High DNA
HBeAg+, fluctuating ALT, fluctuating DNA
HBeAg-, normal ALT, low DNA
HBeAg-, fluctuating ALT, fluctuating DNA
Outcome of chronic infection 15% cirrhosis of which 20% decompensate and 5% get HCC. Cirrhosis is slowly progressive
15% get cirrhosis at 20 years of which 5% decompensate per year, 1% get HCC per year and 4% die per year.
HDV relationship Coinfection -> usually self limited; but⬆ risk of acute liver failure (compared to superinfection).
No increased risk of chronic infection.
None
SuperinfectionALL develop chronic HBV
can present as acute severe hepatitis.
None
Chronic HDV -> rapid progression to cirrhosis. None
HCC association Accounts for 50% of HCC; mostly after onset of cirrhosis. accounts for 20% of HCC; but HCC only occurs after cirrhosis has developed.
⬆viral load increases risk
Immune complexe mediated extrahepatic phenomena are less common in Hep C than in Hep B, except for essential mixed cryoglobulinaemia
Extrahepatic manifestations "Serious Pirates Plundered Nine gold diamond chests" Arthritis, myalgia, Sjogrens, kerato. conj. sicca, Mooren corneal ulcer, porphyria cutanea tarda, lichen planus, asymptomatic mixed cryoglobulinaemia (Type II cgb), membranoproliferative glomerulonephritis
Initially cryoglobulinaemia was described in hepaitits B. Also causes a "mixed cryoglublinaemia". Essential mixed Cryoglobulinaemia is commoner in Hep C:
Mnemonic: C-C. "mixed" means Rheumatoid factor, IgG, Hep C virus RNA and complement.
Treatment 90% clearance rate with treatment!

Painful Painless
Corneal abrasion Lens dislocation
Keratitis Vitreous haemorrhage
Acute Glaucoma Acute maculopathy
Hyphema Retinal detachment
Endophthalmitis Retinal artery occlusion
Anterior Uveitis Retinal Vein occlusion
Optic Neuritis Ischemic optic neuropathy

Hypersensitivity pneumonitis (HP)

Source

Symptoms

Acute Subacute Chronic
Occurs in previously sensitized individuals
Fever, chills (unlike asthma), cough, chest tightness exertional dyspnea, productive cough, fatigue, and weight loss, no fever.
4 - 8 hours after exposure Months to years
Occurs with high level antigen exposure Occurs with low level antigen exposure (like a bird owner)
Physical: fine crackes, NO WHEEZING Can be complicated with cor pulmonale / respiratory failure.
Airway obstruction is unusual Can cause a restrictive pattern

Investigations
CXR - Non specific.
HRCT - profuse, poorly defined centrilobular micronodules is the most characteristic findings. Fibrosis in Chronic HP.
BAL - Lymphocytosis with CD8+ predominance. (lymphocytosis with CD4+ predominant is seen in sarcoidosis)

Treatment:

Side effects of chemotherapy drugs

ToxicityBearChemtherapeuticDrugs.png

cytotoxicAgentsAndSummaries.png